沉默调节蛋白6在肝脏疾病中的作用及其机制

方欢; 钟晓琳

doi:10.3969/j.issn.1001-5256.2021.08.050

沉默调节蛋白6在肝脏疾病中的作用及其机制

DOI: 10.3969/j.issn.1001-5256.2021.08.050

方欢¹,
钟晓琳^2, ,

1.
西南医科大学临床医学院，四川泸州 646000
2.
西南医科大学附属医院消化内科，四川泸州 646000

基金项目:

四川省科技厅基金项目 (2020YJ0190);

王宝恩肝纤维化研究基金项目 (20200520)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：方欢负责收集资料，分析资料，撰写文章及修改文章；钟晓琳负责拟定写作思路，指导撰写文章，修改文章并最后定稿。

详细信息

通信作者:
钟晓琳，34893230@qq.com

中图分类号: R575; R977.6
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- 文章访问数: 492
- HTML全文浏览量: 157
- PDF下载量: 39
- 被引次数: 0
出版历程
- 收稿日期: 2021-01-04
- 录用日期: 2021-02-10
- 出版日期: 2021-08-20

Role and mechanism of SIRT6 in liver diseases

Huan FANG¹,
Xiaolin ZHONG^{2
, ,}

1.
School of Clinical Medicine, Southwest Medical University, Luzhou, Sichuan 646000, China
2.
Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China

Research funding:

Science and Technology Department Foundation of Sichuan Province (2020YJ0190);

WBE Liver Fibrosis Foundation (20200520)

摘要

摘要: 沉默调节蛋白6(SIRT6)具有去乙酰化酶、单ADP核糖基转移酶以及去脂肪酰化酶等多种功能, 在调控多种生理及病理过程中发挥重要作用。概述了SIRT6的结构及生物学功能，详细介绍了SIRT6在病毒性肝炎、非酒精性脂肪性肝病、酒精性脂肪性肝病、肝硬化、肝癌等不同类型的肝脏疾病中的研究进展及相关作用分子机制。了解SIRT6在肝脏疾病中的作用, 可能为肝病的治疗提供新思路及治疗靶点。
- 乙型肝炎, 慢性 /
- 非酒精性脂肪性肝病 /
- 肝硬化 /
- 癌, 肝细胞 /
- 抗衰老酶
Abstract: SIRT6 has the multiple functions of deacetylase, single ADP ribosyltransferase, and defatty acylase and plays an important role in the regulation of various physiological and pathological processes. This article summarizes the structure and biological functions of SIRT6 and introduces in detail the research advances in the role and molecular mechanisms of SIRT6 in different types of liver diseases such as viral hepatitis, nonalcoholic fatty liver, alcoholic fatty liver, liver cirrhosis, and liver cancer. An understanding of the role of SIRT6 in liver diseases may provide new ideas and targets for the treatment of liver diseases.
- Hepatitis B, Chronic /
- Non-Alcoholic Fatty Liver Disease /
- Liver Cirrhosis /
- Carcinoma, Hepatocellular /
- Sirtuins

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参考文献(52)

[1]	ZHONG L, D'URSO A, TOIBER D, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha[J]. Cell, 2010, 140(2): 280-293. DOI: 10.1016/j.cell.2009.12.041.
[2]	KIM HG, HUANG M, XIN Y, et al. The epigenetic regulator SIRT6 protects the liver from alcohol-induced tissue injury by reducing oxidative stress in mice[J]. J Hepatol, 2019, 71(5): 960-969. DOI: 10.1016/j.jhep.2019.06.019.
[3]	KIM HS, XIAO C, WANG RH, et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis[J]. Cell Metab, 2010, 12(3): 224-236. DOI: 10.1016/j.cmet.2010.06.009.
[4]	SEBASTIÁN C, ZWAANS BM, SILBERMAN DM, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism[J]. Cell, 2012, 151(6): 1185-1199. DOI: 10.1016/j.cell.2012.10.047.
[5]	MOSTOSLAVSKY R, CHUA KF, LOMBARD DB, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6[J]. Cell, 2006, 124(2): 315-329. DOI: 10.1016/j.cell.2005.11.044.
[6]	ELHANATI S, KANFI Y, VARVAK A, et al. Multiple regulatory layers of SREBP1/2 by SIRT6[J]. Cell Rep, 2013, 4(5): 905-912. DOI: 10.1016/j.celrep.2013.08.006.
[7]	BLANDER G, GUARENTE L. The Sir2 family of protein deacetylases[J]. Annu Rev Biochem, 2004, 73: 417-435. DOI: 10.1146/annurev.biochem.73.011303.073651.
[8]	FLICK F, LUSCHER B. Regulation of sirtuin function by posttranslational modifications[J]. Front Pharmacol, 2012, 3: 29. DOI: 10.3389/fphar.2012.00029.
[9]	HERSKOVITS AZ, GUARENTE L. Sirtuin deacetylases in neurodegenerative diseases of aging[J]. Cell Res, 2013, 23(6): 746-758. DOI: 10.1038/cr.2013.70.
[10]	MAHLKNECHT U, HO AD, VOELTER-MAHLKNECHT S. Chromosomal organization and fluorescence in situ hybridization of the human Sirtuin 6 gene[J]. Int J Oncol, 2006, 28(2): 447-456.
[11]	PAN PW, FELDMAN JL, DEVRIES MK, et al. Structure and biochemical functions of SIRT6[J]. J Biol Chem, 2011, 286(16): 14575-14587. DOI: 10.1074/jbc.M111.218990.
[12]	JIANG H, KHAN S, WANG Y, et al. SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine[J]. Nature, 2013, 496(7443): 110-113. DOI: 10.1038/nature12038.
[13]	GUO L, WANG D, OUYANG X, et al. Recent advances in HBV reactivation research[J]. Biomed Res Int, 2018, 2018: 2931402. DOI: 10.1155/2018/2931402.
[14]	DU L, MA Y, LIU M, et al. Peroxisome proliferators activated receptor (PPAR) agonists activate hepatitis B virus replication in vivo[J]. Virol J, 2017, 14(1): 96. DOI: 10.1186/s12985-017-0765-x.
[15]	XIE BJ, GUO JJ, ZHANG Y, et al. Peroxisome proliferator-activated receptor alpha regulates HBV minichromosome remodeling and viral replication[J]. J Chongqing Med Univ, 2017, 42(7): 795-802. DOI: 10.13406./j.cnki.cyxb.001349. 谢冰珏, 郭进军, 张燕, 等. 过氧化物酶体增殖物激活受体α(PPARα)调控HBV微染色体重塑与病毒复制[J]. 重庆医科大学学报, 2017, 42(7): 795-802. DOI: 10.13406./j.cnki.cyxb.001349.
[16]	GUIDOTTI LG, EGGERS CM, RANEY AK, et al. In vivo regulation of hepatitis B virus replication by peroxisome proliferators[J]. J Virol, 1999, 73(12): 10377-10386. DOI: 10.1128/JVI.73.12.10377-10386.1999.
[17]	WU XT, YANG J, WANG XJ, et al. Anti-HBV effect identification of antisense oligodeoxynucleotide targeting PPARα[J]. Lett Biotech, 2011, 22(6): 773-776. DOI: 10.3969/j.issn.1009-0002.2011.06.005. 吴小桃, 杨静, 王学军, 等. 抑制核转录因子PPARα的反义寡核苷酸的抗乙型肝炎病毒活性研究[J]. 生物技术通讯, 2011, 22(6): 773-776. DOI: 10.3969/j.issn.1009-0002.2011.06.005.
[18]	JIANG H, CHENG ST, REN JH, et al. SIRT6 inhibitor, OSS_128167 restricts hepatitis B virus transcription and replication through targeting transcription factor peroxisome proliferator-activated receptors α[J]. Front Pharmacol, 2019, 10: 1270. DOI: 10.3389/fphar.2019.01270.
[19]	JIANG H. SIRT6 inhibitor, OSS_128167 effect on hepatitis B virus replication and mechanism of research[D]. Chongqing: Chongqing Medical University, 2020. 姜慧. SIRT6抑制剂, OSS_128167对HBV复制的影响及机制研究[D]. 重庆: 重庆医科大学, 2020.
[20]	YKI-JARVINEN H. Diagnosis of nonalcoholic fatty liver disease (NAFLD)[J]. Duodecim, 2016, 132(22): 2099-2106.
[21]	BUZZETTI E, PINZANI M, TSOCHATZIS EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)[J]. Metabolism, 2016, 65(8): 1038-1048. DOI: 10.1016/j.metabol.2015.12.012.
[22]	ZHOU Q, SU J, JI MY. Progress in the treatment of nonalcoholic fatty liver disease[J]. China Med Herald, 2020, 17(6): 26-29. DOI: 10.3969/j.issn.1000-484X.2019.13.023. 周谦, 苏娟, 季梦遥. 非酒精性脂肪性肝病的治疗研究进展[J]. 中国医药导报, 2020, 17(6): 26-29. DOI: 10.3969/j.issn.1000-484X.2019.13.023.
[23]	KANFI Y, NAIMAN S, AMIR G, et al. The sirtuin SIRT6 regulates lifespan in male mice[J]. Nature, 2012, 483(7388): 218-221. DOI: 10.1038/nature10815.
[24]	PENROSE H, HELLER S, CABLE C, et al. Epidermal growth factor receptor mediated proliferation depends on increased lipid droplet density regulated via a negative regulatory loop with FOXO3/Sirtuin6[J]. Biochem Biophys Res Commun, 2016, 469(3): 370-376. DOI: 10.1016/j.bbrc.2015.11.119.
[25]	XIAO C, KIM HS, LAHUSEN T, et al. SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice[J]. J Biol Chem, 2010, 285(47): 36776-36784. DOI: 10.1074/jbc.M110.168039.
[26]	XIONG X, WANG G, TAO R, et al. Sirtuin 6 regulates glucose-stimulated insulin secretion in mouse pancreatic beta cells[J]. Diabetologia, 2016, 59(1): 151-160. DOI: 10.1007/s00125-015-3778-2.
[27]	XIONG X, SUN X, WANG Q, et al. SIRT6 protects against palmitate-induced pancreatic β-cell dysfunction and apoptosis[J]. J Endocrinol, 2016, 231(2): 159-165. DOI: 10.1530/JOE-16-0317.
[28]	CALIGIURI A, GENTILINI A, MARRA F. Molecular pathogenesis of NASH[J]. Int J Mol Sci, 2016, 17(9)DOI: 10.3390/ijms17091575.
[29]	ZHANG N, LI Z, MU W, et al. Calorie restriction-induced SIRT6 activation delays aging by suppressing NF-κB signaling[J]. Cell Cycle, 2016, 15(7): 1009-1018. DOI: 10.1080/15384101.2016.1152427.
[30]	XIAO C, WANG RH, LAHUSEN TJ, et al. Progression of chronic liver inflammation and fibrosis driven by activation of c-JUN signaling in Sirt6 mutant mice[J]. J Biol Chem, 2012, 287(50): 41903-41913. DOI: 10.1074/jbc.M112.415182.
[31]	DOU HX, ZHANG DJ. Advances in the molecular pathogenesis of alcoholic liver disease[J]. Genom Appl Biol, 2016, 35(7): 1643-1647. DOI: 10.13417/j.gab.035.001643. 窦慧馨, 张得钧. 酒精性肝病分子发病机制研究进展[J]. 基因组学与应用生物学, 2016, 35(7): 1643-1647. DOI: 10.13417/j.gab.035.001643.
[32]	KOURKOUMPETIS T, SOOD G. Pathogenesis of alcoholic liver disease: An update[J]. Clin Liver Dis, 2019, 23(1): 71-80. DOI: 10.1016/j.cld.2018.09.006.
[33]	ZENG T, ZHANG CL, SONG FY, et al. CMZ reversed chronic ethanol-induced disturbance of PPAR-α possibly by suppressing oxidative stress and PGC-1α acetylation, and activating the MAPK and GSK3β pathway[J]. PLoS One, 2014, 9(6): e98658. DOI: 10.1371/journal.pone.0098658.
[34]	XIN SL. SIRT6 alleviates nonalcoholic fatty liver disease by up-regulating PPAR-α pathway and reversing senescence of hepatocytes[D]. Wuhan: Huazhong University of Science and Technology, 2019. 辛晟梁. SIRT6通过上调PPAR-α及阻遏肝细胞衰老改善非酒精性脂肪性肝病[D]. 武汉: 华中科技大学, 2019.
[35]	HIGASHI T, FRIEDMAN SL, HOSHIDA Y. Hepatic stellate cells as key target in liver fibrosis[J]. Adv Drug Deliv Rev, 2017, 121: 27-42. DOI: 10.1016/j.addr.2017.05.007.
[36]	CAJA L, DITURI F, MANCARELLA S, et al. TGF-β and the tissue microenvironment: Relevance in fibrosis and cancer[J]. Int J Mol Sci, 2018, 19(5): 1294. DOI: 10.3390/ijms19051294.
[37]	ZHANG Y, CUI Y, WANG XL, et al. PPARα/γ agonists and antagonists differently affect hepatic lipid metabolism, oxidative stress and inflammatory cytokine production in steatohepatitic rats[J]. Cytokine, 2015, 75(1): 127-135. DOI: 10.1016/j.cyto.2015.05.031.
[38]	ZHANG J, LI Y, LIU Q, et al. Sirt6 alleviated liver fibrosis by deacetylating conserved lysine 54 on Smad2 in hepatic stellate cells[J]. Hepatology, 2021, 73(3): 1140-1157. DOI: 10.1002/hep.31418.
[39]	ZHONG X, HUANG M, KIM HG, et al. SIRT6 protects against liver fibrosis by deacetylation and suppression of SMAD3 in hepatic stellate cells[J]. Cell Mol Gastroenterol Hepatol, 2020, 10(2): 341-364. DOI: 10.1016/j.jcmgh.2020.04.005.
[40]	MAITY S, MUHAMED J, SARIKHANI M, et al. Sirtuin 6 deficiency transcriptionally up-regulates TGF-β signaling and induces fibrosis in mice[J]. J Biol Chem, 2020, 295(2): 415-434. DOI: 10.1074/jbc.RA118.007212.
[41]	TIAN K, CHEN P, LIU Z, et al. Sirtuin 6 inhibits epithelial to mesenchymal transition during idiopathic pulmonary fibrosis via inactivating TGF-β1/Smad3 signaling[J]. Oncotarget, 2017, 8(37): 61011-61024. DOI: 10.18632/oncotarget.17723.
[42]	ZHANG Q, TU W, TIAN K, et al. Sirtuin 6 inhibits myofibroblast differentiation via inactivating transforming growth factor-β1/Smad2 and nuclear factor-κB signaling pathways in human fetal lung fibroblasts[J]. J Cell Biochem, 2019, 120(1): 93-104. DOI: 10.1002/jcb.27128.
[43]	HEIMBACH JK, KULIK LM, FINN RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma[J]. Hepatology, 2018, 67(1): 358-380. DOI: 10.1002/hep.29086.
[44]	ZHAO Y, ZHANG YH. Immunosuppression in hepatocellular carcinoma and immunomodulation in treatment[J]. Chin J Immunol, 2019, 35(13): 1643-1645, 1650. DOI: 10.3969/j.issn.1000-484X.2019.13.023. 赵艳, 张永宏. 肝细胞癌中的免疫抑制与治疗中的免疫调节[J]. 中国免疫学杂志, 2019, 35(13): 1643-1645, 1650. DOI: 10.3969/j.issn.1000-484X.2019.13.023.
[45]	WAHID B, ALI A, RAFIQUE S, et al. New insights into the epigenetics of hepatocellular carcinoma[J]. Biomed Res Int, 2017, 2017: 1609575. DOI: 10.1155/2017/1609575.
[46]	de SOUZA C, CHATTERJI BP. HDAC Inhibitors as novel anti-cancer therapeutics[J]. Recent Pat Anticancer Drug Discov, 2015, 10(2): 145-162. DOI: 10.2174/1574892810666150317144511.
[47]	MIN L, JI Y, BAKIRI L, et al. Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin[J]. Nat Cell Biol, 2012, 14(11): 1203-1211. DOI: 10.1038/ncb2590.
[48]	HUANG Z, ZHAO J, DENG W, et al. Identification of a cellularly active SIRT6 allosteric activator[J]. Nat Chem Biol, 2018, 14(12): 1118-1126. DOI: 10.1038/s41589-018-0150-0.
[49]	van METER M, MAO Z, GORBUNOVA V, et al. SIRT6 overexpression induces massive apoptosis in cancer cells but not in normal cells[J]. Cell Cycle, 2011, 10(18): 3153-3158. DOI: 10.4161/cc.10.18.17435.
[50]	MING M, HAN W, ZHAO B, et al. SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer[J]. Cancer Res, 2014, 74(20): 5925-5933. DOI: 10.1158/0008-5472.CAN-14-1308.
[51]	HAN LL, JIA L, WU F, et al. Sirtuin6 (SIRT6) promotes the EMT of hepatocellular carcinoma by stimulating autophagic degradation of E-cadherin[J]. Mol Cancer Res, 2019, 17(11): 2267-2280. DOI: 10.1158/1541-7786.MCR-19-0321.
[52]	XIA YQ, HUA RJ, JUAN C, et al. SIRT6 depletion sensitizes human hepatoma cells to chemotherapeutics by downregulating MDR1 expression[J]. Front Pharmacol, 2018, 9: 194. DOI: 10.3389/fphar.2018.00194.